Hypoglycemia is a major clinical problem in insulin-treated diabetes. Increased glucagon secretion from pancreatic Aj-cells is a primary defense against hypoglycemia, but glucagon responses to hypoglycemia are impaired in diabetes. The etiology of the impairment is poorly understood, but could involve a failure of the autonomic nervous system (ANS) to stimulate glucagon secretion since the ANS contributes to increased glucagon secretion in several species. However, the role of the ANS in humans is controversial. We investigated the ANS contribution to hypoglycemia-induced glucagon secretion using two pharmacological approaches (blockade of ganglionic neurotransmission with trimethaphan or ANS receptor blockade with atropine + adrenergic antagonists) to impair the ANS imputs to the pancreas in conscious rhesus macaques as a model for human physiology and pathophysiology. We found that the ANS has a major role in mediating the glucagon response during hypoglycemia of 2.0 mmol/L. We are planning further experiments examining the regulation of glucagon secretion during hypoglycemia in normal and diabetic monkeys. Insulin deficiency or insulin resistance contribute to postprandial glycemic excursions in diabetes. The ANS and the gut hormone, GLP-1, may contribute to pancreatic hormone responses to meal ingestion. We have found that plasma pancreatic polypeptide secretion is an index of parasympathetic activation in response to feeding and that the ANS contributed to insulin and glycemic response to food ingestion in normal rhesus monkeys. New experiments are underway to examine the influence of the ANS on neural and hormonal responses in monkeys that are insulin resistant as a result of obesity or after glucocorticoid administration. *KEY*Diabetes, Insulin resistance, Glucagon, Insulin, Pancreatic polypeptide, Glucagone like peptide-1, Norepinephrine, Epinephrine, Trimethaphan, Atropine, Propranolol, Tolazoline